A phase I, first-in-human trial of KO-947, an ERK1/2 inhibitor, in patients with advanced solid tumors
Year: 2025
Type: article
Study design: Clinical Trial
Abstract: BACKGROUND: KO-947, a potent, intravenously administered, extracellular signal-regulated kinase (ERK) inhibitor, has demonstrated activity in preclinical models. This phase I trial of KO-947 evaluated maximum tolerated dose (MTD), safety, and pharmacokinetics in patients with relapsed/refractory solid tumors. MATERIALS AND METHODS: This multicenter, open-label, dose-escalation study evaluated KO-947 0.45-11.3 mg/kg in three schedules. Schedules 1 (0.45-5.4 mg/kg, 1- to 2-hour infusion) and 2 (4.8-9.6 mg/kg, 4-hour infusion) were administered once weekly on a 28-day cycle. Schedule 3 (3.6-11.3 mg/kg, 4-hour infusion) was administered on days 1, 4, and 8 (and on days 11 and 15 for two patients) on a 21-day cycle. The primary objective was determination of MTD and/or recommended phase II dose. Safety analysis included adverse events of special interest (AESIs), namely ocular toxicities and infusion-related reactions (e.g. hypotension, corrected QT interval prolongation). Results from the dose-escalation portion of the phase I study are presented due to trial termination before preplanned cohort expansion cohorts. RESULTS: All 61 enrolled patients (schedules 1/2, n = 34, schedule 3, n = 27) discontinued treatment, mostly owing to disease progression (88% and 67%). The MTD for schedule 1 was 3.6 mg/kg; the maximum administered doses for schedules 2 and 3 were 9.6 and 11.3 mg/kg, respectively. Treatment-related adverse events occurred in 88% of patients in schedules 1/2, and 92% in schedule 3; most common were blurred vision (schedules 1/2, 50.0%; schedule 3, 33.3%). AESIs occurred in 50% of patients in schedules 1/2, and 82% in schedule 3. In all schedules, the best overall response was stable disease. CONCLUSIONS: Intravenous KO-947 had a generally tolerable safety profile with minimal gastrointestinal toxicity compared with oral administration of other ERK inhibitors.
Source: ESMO Open
Language: English
Topic: Melanoma and MAPK Pathways
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,910
Funders: Conquer Cancer Foundation, Amgen, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, GlaxoSmithKline, Sanofi, American Society of Clinical Oncology, Regeneron Pharmaceuticals, Taiho Pharmaceutical, Mersana Therapeutics, BeiGene, Boston Pharmaceuticals, Incyte, Relay Therapeutics, Puma Biotechnology, MacroGenics, Astellas Pharma, Shionogi, Genentech, Takeda Oncology, Loxo Oncology, Principia Biopharma, National Cancer Institute, Janssen Pharmaceuticals, Daiichi Sankyo Europe
OpenAlex ID: W4407803933